In Vivo Nano-imaging of Membrane Dynamics in Metastatic Tumor Cells Using Quantum Dots (original) (raw)
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Motility cues in the tumor microenvironment
Differentiation, 2002
It is now increasingly recognized that the microenvironment plays a critical role in the progression of tumors. Perhaps less obvious is the concept that the microenvironment may share responsibility in determining the ''malignant'' traits of tumor cells, i.e. invasiveness and metastasis. If tumors are tissues, however unbalanced, rather than a collection of ''malignant'' cells recruiting local resources for the purpose of growth, then it is inevitable that tumor cells will respond to local stimuli. These stimuli include cues for motility and migration, which normally appear in tissues undergoing formation, remodeling or healing. Carcinoma cells are likely to be sensitive to the motility cues that normally regulate epithelial morphogenetic movements such as ingression, delamination, invagination, and tube or sheet migration. ''Malignant'' tumors, then, can be redefined as those in which these cues arise more frequently or act more effectively. Here, we expand on this view and propose that invasion and metastasis may be the outcome of tumor cell responses to microenvironmental motility cues. Understanding how such motility cues arise and act, both in normal and tumor tissue, should be a high priority in cancer research.
Physiological Mechanisms of Tumor-Cell Invasion and Migration
Physiology, 2005
complicated progression as cancer cells conspire with their local environment to grow, survive, and metastasize (FIGURE 2). Each of the steps involved in tumor metastasis requires numerous specific molecular interactions contributed by the tumor cell and the surrounding extracellular matrix (ECM) and stromal cells (35). These interactions are mediated by contact between the cell and the ECM, by direct cell-cell contact, and by secreted factors. Tumor Cell Migration Through Tissue Microenvironments Three-dimensional (3-D) molecular contacts, contributed by the basement membrane, ECM, and adjacent cells, provide an architectural context within which a normal cell functions. Adhesive structures are physical connections between the cytoskeleton (CSK) and the ECM (an extracellularmatrix connection) or between the CSK and the CSK of other cells (a cell-cell connection). There are several adhesion receptor families, including selectins, syndecans, the immunoglobulin cell adhesion molecules, cadherins, and integrins. The best-studied adhesion receptors, and of particular interest in migration, are the 194 1548-9213/05 8.00 ©2005 Int. Union Physiol. Sci./Am. Physiol. Soc. Numerous molecular hurdles stand between a newly invasive tumor cell and its distant new home in another organ. The rigor of the journey is reflected by the finding that <0.05% of circulating tumor cells are actually able to become stable metastases (34). The metastatic sequence is understood to involve detachment of cells within a primary tumor, local migration and invasion of stromal tissue, intravasation and transit through blood vessels, capillary bed arrest and extravasation, further local crawling and invasion, attachment, formation of micrometastases, survival, perhaps dormancy, and eventually further proliferation (FIGURE 1) (6, 64). To overcome this remarkable set of challenges, the invasive cancer cell must borrow a molecular apparatus, or infrastructure, that normally enables important physiological functions, such as morphogenesis (58), neurogenesis (66), and angiogenesis (14). These examples of invasion are under exquisite control and facilitate the development and homeostasis of an organism. In marked contrast, metastatic tumor cells prey upon these molecular systems, often leading to organismal demise (37). Numerous interactions underlie this
Current Opinion in Cell Biology, 2005
Invasion of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane and its attachment to the extracellular matrix. Recent advances in intravital imaging and the development of an in vivo invasion assay have provided new insights into how cancer cell migration is regulated by elements of the local microenvironment, including the extracellular matrix architecture and other cell types found in primary tumors. These results, combined with new findings from in vitro studies, have led to new insights into the molecular mechanisms of cell protrusive activity and chemotactic migration during invasion and metastasis.
Compensation mechanism in tumor cell migration
The Journal of Cell Biology, 2003
nvasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor-based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of  1 integrins and MT1-matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted I from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered  1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.
Contractile forces in tumor cell migration
European Journal of Cell Biology, 2008
Cancer is a deadly disease primarily because of the ability of tumor cells to spread from the primary tumor, to invade into the connective tissue, and to form metastases at distant sites. In contrast to cell migration on a planar surface where large cell tractions and contractile forces are not essential, tractions and forces are thought to be crucial for overcoming the resistance and steric hindrance of a dense 3-dimensional connective tissue matrix. In this review, we describe recently developed biophysical tools including 2-D and 3-D traction microscopy to measure contractile forces of cells. We discuss evidence indicating that tumor cell invasiveness is associated with increased contractile force generation. Cell migration and invasion The main reason for the malignancy of cancer is the ability of tumor cells to form secondary tumors and metastasize in distant organs. To form metastases, cancer cells need to take multiple steps: First, they separate from the primary tumor and invade through the tissue and the extracellular matrix. Next, they enter a nearby blood and lymph vessel where they get transported to distant sites. The subsequent steps are in dispute, but a likely scenario is that the cancer cells adhere onto the endothelium of the vessel, transmigrate through the endothelium and, once more, migrate through the tissue. Regardless of whether extravasation takes place, however, the migration through connective tissue (subsequently called invasion) is a prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix-degrading enzymes, have become the focus of research (Paszek et al., 2005; Rolli et al., 2003; Wolf et al., 2003). However, the mechanical processes themselves that control cancer cell invasion, such as cell adhesion, changes of cell shape, cell movements and motility, and the generation of forces, are currently not well understood (Friedl and Brocker, 2000; Ridley et al., 2003; Zaman et al., 2006). In particular, some of the most elementary questions regarding the forces during cancer cell invasion have not yet been answered: Do cells push against the tissue to propel themselves forward, or do they grab tissue matrix in front of them and then pull? How hard do they push or pull? How
PLOS One, 2010
Cell migration is a fundamental feature of the interaction of cells with their surrounding. The cell's stiffness and ability to deform itself are two major characteristics that rule migration behavior especially in three-dimensional tissue. We simulate this situation making use of a micro-fabricated migration chip to test the active invasive behavior of pancreatic cancer cells (Panc-1) into narrow channels. At a channel width of 7 mm cell migration through the channels was significantly impeded due to size exclusion. A striking increase in cell invasiveness was observed once the cells were treated with the bioactive lipid sphingosylphosphorylcholine (SPC) that leads to a reorganization of the cell's keratin network, an enhancement of the cell's deformability, and also an increase in the cell's migration speed on flat surfaces. The migration speed of the highly deformed cells inside the channels was three times higher than of cells on flat substrates but was not affected upon SPC treatment. Cells inside the channels migrated predominantly by smooth sliding while maintaining constant cell length. In contrast, cells on adhesion mediating narrow lines moved in a stepwise way, characterized by fluctuations in cell length. Taken together, with our migration chip we demonstrate that the dimensionality of the environment strongly affects the migration phenotype and we suggest that the spatial cytoskeletal keratin organization correlates with the tumor cell's invasive potential.
Tumor cell migration in complex microenvironments
Cellular and Molecular Life Sciences, 2013
Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.
Tumour-cell invasion and migration: diversity and escape mechanisms
Nature Reviews Cancer, 2003
The ability of a cancer cell to undergo migration and INVASION allow it to change position within the tissues. For example, these processes allow neoplastic cells to enter lymphatic and blood vessels for dissemination into the circulation, and then undergo metastatic growth in distant organs 1 . To spread within the tissues, tumour cells use migration mechanisms that are similar, if not identical, to those that occur in normal, non-neoplastic cells during physiological processes such as embryonic morphogenesis, would healing and immune-cell trafficking 2 . The principles of cell migration were initially investigated in non-neoplastic fibroblasts, keratinocytes and myoblasts 3,4 , but additional studies on tumour cells show that the same basic strategies are retained.
Biomechanics of transendothelial migration by cancer cells
BIOCELL
Cancer metastasis is still a major social issue with limited knowledge of the formation of tumors and their growth. In addition the formation of metastases is very difficult to understand, since it involves very complex physical mechanisms such as cellular interactions and cell rheology, which are flow-dependent. Previous studies investigated transendothelial migration using sophisticated techniques such as microfluidics, traction force microscopy (TFM) or Atomic Force Microscopy (AFM), combined with physical modeling. Here we summarize recent results and suggest new ways to investigate the precise mechanisms used by cancer cells to undergo transendothelial migration.
Cold Spring Harbor symposia on quantitative biology, 2016
Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients. These gradients form through dynamic interactions between the tumor cells and the resident fibroblasts, adipocytes, nerves, endothelial cells, infiltrating immune cells, and mesenchymal stem cells. Malignant progression results from ...